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Reducing calorie intake without malnutrition limits tumor progression but the underlying mechanisms are poorly understood. Here we show that dietary restriction (DR) suppresses tumor growth by enhancing CD8 + T cell-mediated anti-tumor immunity. DR reshapes CD8 + T cell differentiation within the tumor microenvironment (TME), promoting the development of effector T cell subsets while limiting the accumulation of exhausted T (Tex) cells, and synergizes with anti-PD1 immunotherapy to restrict tumor growth. Mechanistically, DR enhances CD8 + T cell metabolic fitness through increased ketone body oxidation (ketolysis), which boosts mitochondrial membrane potential and fuels tricarboxylic acid (TCA) cycle-dependent pathways essential for T cell function. T cells deficient for ketolysis exhibit reduced mitochondrial function, increased exhaustion, and fail to control tumor growth under DR conditions. Our findings reveal a critical role for the immune system in mediating the anti-tumor effects of DR, highlighting nutritional modulation of CD8 + T cell fate in the TME as a critical determinant of anti-tumor immunity.

Cancer cells are exposed to diverse metabolites in the tumor microenvironment that are used to support the synthesis of nucleotides, amino acids, and lipids needed for rapid cell proliferation 1-3 . Recent work has shown that ketone bodies such as β-hydroxybutyrate (β-OHB), which are elevated in circulation under fasting conditions or low glycemic diets, can serve as an alternative fuel that is metabolized in the mitochondria to provide acetyl-CoA for the tricarboxylic acid (TCA) cycle in some tumors 4-7 . Here, we discover a non-canonical route for β-OHB metabolism, in which β-OHB can bypass the TCA cycle to generate cytosolic acetyl-CoA for de novo fatty acid synthesis in cancer cells. We show that β-OHB-derived acetoacetate in the mitochondria can be shunted into the cytosol, where acetoacetyl-CoA synthetase (AACS) and thiolase convert it into acetyl-CoA for fatty acid synthesis. This alternative metabolic routing of β-OHB allows it to avoid oxidation in the mitochondria and net contribute to anabolic biosynthetic processes. In cancer cells, β-OHB is used for fatty acid synthesis to support cell proliferation under lipid-limited conditions in vitro and contributes to tumor growth under lipid-limited conditions induced by a calorie-restricted diet in vivo . Together, these data demonstrate that β-OHB is preferentially used for fatty acid synthesis in cancer cells to support tumor growth., Competing Interests: Competing interests: R.G.J. is a scientific advisor to Servier Pharmaceuticals and is a member of the Scientific Advisory Board of Immunomet Therapeutics. All other authors declare no competing interests.

Glucose is essential for T cell proliferation and function, yet its specific metabolic roles in vivo remain poorly defined. Here, we identify glycosphingolipid (GSL) biosynthesis as a key pathway fueled by glucose that enables CD8 + T cell expansion and cytotoxic function in vivo . Using 13 C-based stable isotope tracing, we demonstrate that CD8 + effector T cells use glucose to synthesize uridine diphosphate-glucose (UDP-Glc), a precursor for glycogen, glycan, and GSL biosynthesis. Inhibiting GSL production by targeting the enzymes UGP2 or UGCG impairs CD8 + T cell expansion and cytolytic activity without affecting glucose-dependent energy production. Mechanistically, we show that glucose-dependent GSL biosynthesis is required for plasma membrane lipid raft integrity and aggregation following TCR stimulation. Moreover, UGCG-deficient CD8 + T cells display reduced granzyme expression and tumor control in vivo . Together, our data establish GSL biosynthesis as a critical metabolic fate of glucose-independent of energy production-required for CD8 + T cell responses in vivo ., Competing Interests: DECLARATION OF INTERESTS R.G.J. is a scientific advisor to Servier Pharmaceuticals and is a member of the Scientific Advisory Board of Immunomet Therapeutics.

There has long existed a substantial disparity in access to radiotherapy globally. This issue has only been exacerbated as the growing disparity of cancer incidence between high-income countries (HIC) and low and middle-income countries (LMICs) widens, with a pronounced increase in cancer cases in LMICs. Even within HICs, iniquities within local communities may lead to a lack of access to care. Due to these trends, it is imperative to find solutions to narrow global disparities. This requires the engagement of a diverse cohort of stakeholders, including working professionals, non-governmental organizations, nonprofits, professional societies, academic and training institutions, and industry. This review brings together a diverse group of experts to highlight critical areas that could help reduce the current global disparities in radiation oncology. Advancements in technology and treatment, such as artificial intelligence, brachytherapy, hypofractionation, and digital networks, in combination with implementation science and novel funding mechanisms, offer means for increasing access to care and education globally. Common themes across sections reveal how utilizing these new innovations and strengthening collaborative efforts among stakeholders can help improve access to care globally while setting the framework for the next generation of innovations., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: The relationship of sarcopenia to frailty and other survival determinants in patients waitlisted for kidney transplant is not well characterized. Our goal was to evaluate the relationship of muscle area to functional and frailty metrics and its impact on survival in patients waitlisted for kidney transplant., Methods: Among 303 consecutively listed transplant candidates, 172 had a computed scan within 3 months of frailty and biochemical testing that permitted muscle area evaluation. Third lumbar level psoas muscle indices (total bilateral psoas area/height 2 ) were calculated. Testing included frailty metrics, treadmill and pedometer ability, troponin, and brain natriuretic peptide levels. Associations between muscle area, demographic, biochemical, and frailty measures were analyzed. Log-rank test was used to evaluate waitlist survival on the basis of muscle area, and multivariate Cox proportional hazards modeling was used to evaluate factors independently associated with survival., Results: Demographic factors associated with third lumbar level psoas muscle indices include male sex (P < .001), race (P = .02), age (P = .004), and body mass index (P < .0001). Grip strength, treadmill ability, and Sit-Stands positively correlated with third lumbar level psoas muscle indices (P < .01). Brain natriuretic peptide and Up and Go negatively correlated with third lumbar level psoas muscle indices (P < .01). Survival was significantly associated with third lumbar level psoas muscle indices (P = 0.02). Treadmill ability, Sit-Stands, Up and Go, race and muscle area were most closely associated with waitlist survival on multivariate modeling., Conclusion: Sarcopenia as assessed with muscle area measurements is independently associated with kidney waitlist survival. Functional ability and muscle area may be overlapping, but noncongruent, determinants of waitlist outcomes and may need to be individually assessed to create the most predictive survival model., Competing Interests: Conflict of Interest/Disclosure Dr Katz reports commercial research support for immunosuppression drug trials from Bristol Myers Squibb and participation in the Hansa Biopharma ConfideS imlifidase trial in highly sensitized transplant candidates. Dr Kalil reports a research grant from Eurofins. All other authors declare no potential conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: To evaluate for the first time, comparative serum and prostate tissue concentrations of lipophilic and hydrophilic statins., Methods: After reviewing all patients who underwent radical prostatectomy between 1993 and 2019, we selected 80 patients taking atorvastatin (lipophilic) or rosuvastatin (hydrophilic) for cholesterol control and with available banked fresh-frozen tissue from the prostatectomy. Primary endpoint was serum and prostate statin concentration measured by HPLC-mass spectrometry analysis. Serum/prostate statin concentrations were compared between patients on atorvastatin and rosuvastatin, and patients receiving high- and low-dose statin, using the Mann-Whitney U test., Results: In total, 39 patients were taking atorvastatin and 41 were taking rosuvastatin. Thirty-eight and 42 were taking high- and low-dose statin, respectively. Statin concentration was measurable in the prostatic tissue of 15 patients (38.4%) taking atorvastatin (33.3% high-dose vs 42.8% low-dose) compared to 22 (53.6%) taking rosuvastatin (55% high-dose vs 52.3% low-dose). Median tissue concentration of rosuvastatin was greater than atorvastatin (3.98 ng/g vs 0.96 ng/g, P <.001). Dose-dependency was observed: median prostate concentration was higher in those taking high-dose versus low-dose statin for both atorvastatin (1.22 ng/g vs 0.79 ng/g, P = .69) and rosuvastatin (5.21 ng/g vs 1.99 ng/g, P <.001)., Conclusion: We have shown, for the first time, that lipophilic and hydrophilic statins can be measured in the prostate of patients with prostate cancer and that the concentrations are dependent on dose. Moreover, rosuvastatin, a hydrophilic statin, achieves a 4-fold higher concentration in the prostate., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The progressive decline of CD8 T cell effector function-also known as terminal exhaustion-is a major contributor to immune evasion in cancer. Yet, the molecular mechanisms that drive CD8 T cell dysfunction remain poorly understood. Here, we report that the Kelch-like ECH-associated protein 1 (KEAP1)-Nuclear factor erythroid 2-related factor 2 (NRF2) signaling axis, which mediates cellular adaptations to oxidative stress, directly regulates CD8 T cell exhaustion. Transcriptional profiling of dysfunctional CD8 T cells from chronic infection and cancer reveals enrichment of NRF2 activity in terminally exhausted (Tex term ) CD8 T cells. Increasing NRF2 activity in CD8 T cells (via conditional deletion of KEAP1) promotes increased glutathione production and antioxidant defense yet accelerates the development of terminally exhausted (PD-1 + TIM-3 + ) CD8 T cells in response to chronic infection or tumor challenge. Mechanistically, we identify PTGIR, a receptor for the circulating eicosanoid prostacyclin, as an NRF2-regulated protein that promotes CD8 T cell dysfunction. Silencing PTGIR expression restores the anti-tumor function of KEAP1-deficient T cells. Moreover, lowering PTGIR expression in CD8 T cells both reduces terminal exhaustion and enhances T cell effector responses (i.e. IFN-γ and granzyme production) to chronic infection and cancer. Together, these results establish the KEAP1-NRF2 axis as a metabolic sensor linking oxidative stress to CD8 T cell dysfunction and identify the prostacyclin receptor PTGIR as an NRF2-regulated immune checkpoint that regulates CD8 T cell fate decisions between effector and exhausted states., Competing Interests: Competing interests: RGJ is a scientific advisor for Servier Pharmaceuticals and is a member of the Scientific Advisory Board of Immunomet Therapeutics.

Infusion of 13 C-labeled metabolites provides a gold standard for understanding the metabolic processes used by T cells during immune responses in vivo. Through infusion of 13 C-labeled metabolites (glucose, glutamine, and acetate) in Listeria monocytogenes -infected mice, we demonstrate that CD8 T effector (Teff) cells use metabolites for specific pathways during specific phases of activation. Highly proliferative early Teff cells in vivo shunt glucose primarily toward nucleotide synthesis and leverage glutamine anaplerosis in the tricarboxylic acid (TCA) cycle to support adenosine triphosphate and de novo pyrimidine synthesis. In addition, early Teff cells rely on glutamic-oxaloacetic transaminase 1 (Got1)-which regulates de novo aspartate synthesis-for effector cell expansion in vivo. CD8 Teff cells change fuel preference over the course of infection, switching from glutamine- to acetate-dependent TCA cycle metabolism late in infection. This study provides insights into the dynamics of Teff metabolism, illuminating distinct pathways of fuel consumption associated with CD8 Teff cell function in vivo.

Patients with the autosomal dominant tumor susceptibility syndrome neurofibromatosis type 1 (NF1) commonly develop plexiform neurofibromas (PNs) that subsequently transform into highly aggressive malignant peripheral nerve sheath tumors (MPNSTs). Understanding the process by which a PN transforms into an MPNST would be facilitated by the availability of genetically engineered mouse (GEM) models that accurately replicate the PN-MPNST progression seen in humans with NF1. Unfortunately, GEM models with Nf1 ablation do not fully recapitulate this process. This led us to develop P0-GGFβ3 mice, a GEM model in which overexpression of the Schwann cell mitogen neuregulin-1 (NRG1) in Schwann cells results in the development of PNs that progress to become MPNSTs with high frequency. However, to determine whether tumorigenesis and neoplastic progression in P0-GGFβ3 mice accurately model the processes seen in NF1 patients, we had to first prove that the pathology of P0-GGFβ3 peripheral nerve sheath tumors recapitulates the pathology of their human counterparts. Here, we describe the specialized methodologies used to accurately diagnose and grade peripheral nervous system neoplasms in GEM models, using P0-GGFβ3 and P0-GGFβ3;Trp53 +/- mice as an example. We describe the histologic, immunohistochemical, and histochemical methods used to diagnose PNs and MPNSTs, how to distinguish these neoplasms from other tumor types that mimic their pathology, and how to grade these neoplasms. We discuss the establishment of early-passage cultures from GEM MPNSTs, how to characterize these cultures using immunocytochemistry, and how to verify their tumorigenicity by establishing allografts. Collectively, these techniques characterize the pathology of PNs and MPNSTs that arise in GEM models and critically compare the pathology of these murine tumors to their human counterparts.

Amino-terminal (Nt-) acetylation (NTA) is a common protein modification, affecting approximately 80% of all human proteins. The human essential X-linked gene, NAA10, encodes for the enzyme NAA10, which is the catalytic subunit in the N-terminal acetyltransferase A (NatA) complex. There is extensive genetic variation in humans with missense, splice-site, and C-terminal frameshift variants in NAA10. In mice, Naa10 is not an essential gene, as there exists a paralogous gene, Naa12, that substantially rescues Naa10 knockout mice from embryonic lethality, whereas double knockouts (Naa10-/Y Naa12-/-) are embryonic lethal. However, the phenotypic variability in the mice is nonetheless quite extensive, including piebaldism, skeletal defects, small size, hydrocephaly, hydronephrosis, and neonatal lethality. Here we replicate these phenotypes with new genetic alleles in mice, but we demonstrate their modulation by genetic background and environmental effects. We cannot replicate a prior report of "maternal effect lethality" for heterozygous Naa10-/X female mice, but we do observe a small amount of embryonic lethality in the Naa10-/y male mice on the inbred genetic background in this different animal facility., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Lyon et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Targeting programmed cell death protein 1 (PD-1) is an important component of many immune checkpoint blockade (ICB) therapeutic approaches. However, ICB is not an efficacious strategy in a variety of cancer types, in part due to immunosuppressive metabolites in the tumor microenvironment. Here, we find that αPD-1-resistant cancer cells produce abundant itaconate (ITA) due to enhanced levels of aconitate decarboxylase (Acod1). Acod1 has an important role in the resistance to αPD-1, as decreasing Acod1 levels in αPD-1-resistant cancer cells can sensitize tumors to αPD-1 therapy. Mechanistically, cancer cells with high Acod1 inhibit the proliferation of naive CD8 + T cells through the secretion of inhibitory factors. Surprisingly, inhibition of CD8 + T cell proliferation is not dependent on the secretion of ITA but is instead a consequence of the release of small inhibitory peptides. Our study suggests that strategies to counter the activity of Acod1 in cancer cells may sensitize tumors to ICB therapy., Competing Interests: Declaration of interests R.G.J. is a scientific advisor for Agios Pharmaceuticals and Servier Pharmaceuticals and is a member of the scientific advisory board of ImmunoMet Therapeutics., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Uncertainty is a universal experience of family caregivers caring for persons with a stroke and affects caregivers' readiness to care for their family members with a stroke. Guided by the unitary caring theory and unitary-caring hermeneutic-phenomenological research method, this study was conducted among 15 family caregivers of persons in the hospital who have survived strokes through in-depth semi-structured interviews. Five essences emerged from the analysis: living in a dark reality; yearning for professional support; enduring a life full of tribulations; attempting resolution; and creating new patterns of living. Each of the 5 essences was interpreted from Smith's unitary caring theory perspective., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Proteostasis requires oxidative metabolism (ATP) and mitigation of the associated damage by glutathione, in an increasingly dysfunctional relationship with aging. SLC3A2 (4F2hc, CD98) plays a role as a disulfide-linked adaptor to the SLC7A5 and SLC7A11 exchangers which import essential amino acids and cystine while exporting Gln and Glu, respectively. The positions of N-glycosylation sites on SLC3A2 have evolved with the emergence of primates, presumably in synchrony with metabolism. Herein, we report that each of the four sites in SLC3A2 has distinct profiles of Golgi-modified N-glycans. N-glycans at the primate-derived site N381 stabilized SLC3A2 in the galectin-3 lattice against coated-pit endocytosis, while N365, the site nearest the membrane promoted glycolipid-galectin-3 (GL-Lect)-driven endocytosis. Our results indicate that surface retention and endocytosis are precisely balanced by the number, position, and remodeling of N-glycans on SLC3A2. Furthermore, proteomics and functional assays revealed an N-glycan-dependent clustering of the SLC3A2∗SLC7A5 heterodimer with amino-acid/Na + symporters (SLC1A4, SLC1A5) that balances branched-chain amino acids and Gln levels, at the expense of ATP to maintain the Na + /K + gradient. In replete conditions, SLC3A2 interactions require Golgi-modified N-glycans at N365D and N381D, whereas reducing N-glycosylation in the endoplasmic reticulum by fluvastatin treatment promoted the recruitment of CD44 and transporters needed to mitigate stress. Thus, SLC3A2 N-glycosylation and Golgi remodeling of the N-glycans have distinct roles in amino acids import for growth, maintenance, and metabolic stresses., Competing Interests: Conflicts of interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Environmental nutrient availability influences T cell metabolism, impacting T cell function and shaping immune outcomes. Here, we identified ketone bodies (KBs)-including β-hydroxybutyrate (βOHB) and acetoacetate (AcAc)-as essential fuels supporting CD8 + T cell metabolism and effector function. βOHB directly increased CD8 + T effector (Teff) cell cytokine production and cytolytic activity, and KB oxidation (ketolysis) was required for Teff cell responses to bacterial infection and tumor challenge. CD8 + Teff cells preferentially used KBs over glucose to fuel the tricarboxylic acid (TCA) cycle in vitro and in vivo. KBs directly boosted the respiratory capacity and TCA cycle-dependent metabolic pathways that fuel CD8 + T cell function. Mechanistically, βOHB was a major substrate for acetyl-CoA production in CD8 + T cells and regulated effector responses through effects on histone acetylation. Together, our results identify cell-intrinsic ketolysis as a metabolic and epigenetic driver of optimal CD8 + T cell effector responses., Competing Interests: Declaration of interests R.G.J. is a scientific advisor for Agios Pharmaceuticals and Servier Pharmaceuticals and is a member of the Scientific Advisory Board of Immunomet Therapeutics., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The emergence and spread of multidrug-resistant tuberculosis (MDR-TB) presents a challenge to the "End TB by 2035" strategy. This study aimed to identify the risk factors associated with MDR-TB in patients admitted to the pneumo-physiology clinic of the National University Hospital of Bangui in Central African Republic., Methods: This was a "retrospective" chart review study. Cases were represented by patients more than 18 years of age treated for MDR-TB and controls were patients with "at least rifampicin-susceptible" TB treated "with first-line anti-TB regimen" and who at the end of treatment were declared cured. The status of "cured" was exclusively applicable to non-MDR TB. Risk factors associated with MDR-TB were identified by multivariate analysis., Results: We included 70 cases and 140 controls. The median age was 35 years, IQR (22;46 years). The main factors associated with the occurrence of MDR-TB in multivariate analysis were male gender (0 R = 3.02 [1.89-3.99], p = 0.001), residence in a peri-urban/urban area (0 R = 3.06 [2.21-4.01], p = 0.002), history of previous TB treatment (0 R= 3.99 [2.77-4.25], p < 0.001) and the presence of multidrug-resistant TB in the family (0 R=1.86 [1.27-2.45], p = 0.021)., Conclusion: The emergence of MDR-TB can be reduced by implementing appropriate strategies, such as preventive therapy in contacts of MDR-TB patients and detecting and appropriately treating MDR-TB patients to prevent further spread of infection., Competing Interests: Declaration of Competing Interest We have no conflict of interest to declare., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Person- and family-centered care is one of the recommendations to achieve quality of care and patient safety. However, many health professionals associate the family with insecurity in care., Objective: To analyze, based on nurses' statements, the advantages and disadvantages of the family's presence in hospitals for the safety of hospitalized patients., Methods: This was a qualitative interpretative study based on James Reason's risk model, conducted through semi-structured interviews with 10 nurses selected by convenience. A content analysis was performed using Bardin's methodology and MAXQDA Plus 2022 software., Results: We identified 17 categories grouped according to the representation of the family in patient safety: The family as a Potentiator of Security Failures (7) and Family as a Safety Barrier (10)., Conclusions: The higher number of categories identified under Family as a Safety Barrier shows that nurses see strong potential in the family's involvement in patient safety. By identifying the need to intervene with and for families so that their involvement is safe, we observed an increase in the complexity of nursing care, which suggests the need to improve nursing ratios, according to the participants.

Evidence highlights the need for professionals to be aware of their stigmatizing attitudes and discriminatory practices in order to minimize the negative impact on the people they take care of. However, nursing students' perceptions of these issues have been poorly studied. This study explores the perspective of senior undergraduate nursing students on mental health and the stigma around it, by considering a simulated case vignette of a person with a mental health problem. A descriptive qualitative approach was chosen and involved three online focus group discussions. The findings show various manifestations of stigma, both at an individual and collective level, which indicates that it is an obstacle to the wellbeing of people with mental illness. Individual manifestations of stigma concern its effect on the person with mental illness, while at the collective level they concern the family or society in general. Stigma is a multifactorial, multidimensional, and complex concept, in terms of identifying and fighting it. Thus, the strategies identified involve multiple approaches at the individual level, aimed at the patient and family, namely through education/training, communication, and relationship strategies. At the collective level, to intervene with the general population and specific groups, such as groups of young people, strategies suggested include education/training, use of the media, and contact with people with mental disorders as ways to fight stigma.

The genus Ulex comprises thirteen accepted species of perennial shrubs in the family Fabaceae. In Galicia (Spain) many of these are considered spontaneous colonizing species, which are easy to establish and maintain. Among them, Ulex gallii Planch. is used in traditional medicine for the same anti-infective, hypotensive and diuretic purposes as Ulex europaeus L., which is the most studied species. Likewise, some studies have described the antitumoral properties of several species. However, there are few scientific studies that justify the use of Ulex gallii Planch. and nothing has been reported about its composition to date. In our study, the entire plant was extracted with methanol and the crude extract was subjected to liquid phase extraction with distinct solvents, yielding three fractions: hexane (H), dichloromethane (D) and methanol (M), which were subsequently fractionated. The dichloromethane (D5, D7 and D8) and methanol (M4) sub-fractions showed antiproliferative activity on A549 (lung cancer) and AGS (stomach cancer) cell lines, and caspase 3/7 activity assessment and DNA quantification were also performed. Targeted analysis via UHPLC-QToF, in combination with untargeted analysis via MS-Dial, MS-Finder and Global Natural Products Social Molecular Networking (GNPS), allowed us to tentatively identify different metabolites in these sub-fractions, mostly flavonoids, that might be involved in their antiproliferative activity.

To better prepare for a potential future pandemic, it is important to investigate factors that influenced responses to the recent COVID-19 pandemic. The aim of the present study was to investigate factors that influenced the decision to get the COVID-19 vaccine. The COVID-19 pandemic has affected almost everyone throughout the world. Vaccines are a significant factor in managing a pandemic. As vaccines are developed, governments develop vaccine roll-out plans. Unfortunately, vaccine hesitancies can slow the implementation of any vaccine program. A question arises as to the factors that are associated with the decision to get vaccinated. The present study explored associations between vaccine hesitancy, and the Health Belief Model (HBM) in student samples from the Czech Republic, Israel, and the United States. From August, 2021 through December, 2021, an online survey was distributed in Czech, Hebrew, and English. A total of 447 participants completed the survey. A binomial logistic regression was conducted to ascertain the influence of perceived susceptibility, severity, benefits, and barriers on the likelihood that participants are vaccinated. Results revealed that the factors of perceived severity and perceived benefits explained 52.6% (Nagelkerke R 2 ) of the variance in vaccination. An analysis of Variance (ANOVA) found significant differences between countries for the 4 HBM factors. Based on these findings, it is recommended that policymakers put forth added emphasis on the severity of a virus and the benefits associated with the vaccine. Further, since there appears to be variability between countries in perceptions of the virus, and associated vaccine, governments should consider factors within their own environment when developing a strategy to combat a pandemic. More specifically, government could explore their own strengths, weaknesses, opportunities, and threats as they develop a pandemic strategy. Additional practical and theoretical implications are discussed.

Due to the need for new chemical entities for cardiovascular diseases, we have synthesized a new series of nitrate-coumarins and evaluated their vasorelaxant activity in contraction-relaxation studies using rat aorta rings precontracted with phenylephrine or by depolarization with a high concentration of potassium chloride. Four of the new compounds were able to relax smooth vascular muscle with a similar profile and potency to glyceryl trinitrate (IC 50 =12.73 nM) and sodium nitroprusside (IC 50 =4.32 nM). Coumarin-7-yl-methyl nitrate (4), the best compound within the series, was able to relax smooth vascular muscle in the low nanomolar range (IC 50 =1.92 nM). The mechanisms of action have been explored, being the activation of sGC and the opening of K + channels involved. Our studies indicate that the new nitrate derivatives are reversible and not deleterious for aortic rings, suggesting that these compounds have a potential interest for the development of new and highly efficient vasodilator drugs., (© 2022 The Authors. ChemMedChem published by Wiley-VCH GmbH.)

Statins, a family of FDA-approved cholesterol-lowering drugs that inhibit the rate-limiting enzyme of the mevalonate metabolic pathway, have demonstrated anticancer activity. Evidence shows that dipyridamole potentiates statin-induced cancer cell death by blocking a restorative feedback loop triggered by statin treatment. Leveraging this knowledge, we develop an integrative pharmacogenomics pipeline to identify compounds similar to dipyridamole at the level of drug structure, cell sensitivity and molecular perturbation. To overcome the complex polypharmacology of dipyridamole, we focus our pharmacogenomics pipeline on mevalonate pathway genes, which we name mevalonate drug-network fusion (MVA-DNF). We validate top-ranked compounds, nelfinavir and honokiol, and identify that low expression of the canonical epithelial cell marker, E-cadherin, is associated with statin-compound synergy. Analysis of remaining prioritized hits led to the validation of additional compounds, clotrimazole and vemurafenib. Thus, our computational pharmacogenomic approach identifies actionable compounds with pathway-specific activities., (© 2022. The Author(s).)

How environmental nutrient availability impacts T cell metabolism and function remains poorly understood. Here, we report that the presence of physiologic carbon sources (PCSs) in cell culture medium broadly impacts glucose utilization by CD8 + T cells, independent of transcriptional changes in metabolic reprogramming. The presence of PCSs reduced glucose contribution to the TCA cycle and increased effector function of CD8 + T cells, with lactate directly fueling the TCA cycle. In fact, CD8 + T cells responding to Listeria infection preferentially consumed lactate over glucose as a TCA cycle substrate in vitro, with lactate enhancing T cell bioenergetic and biosynthetic capacity. Inhibiting lactate-dependent metabolism in CD8 + T cells by silencing lactate dehydrogenase A (Ldha) impaired both T cell metabolic homeostasis and proliferative expansion in vivo. Together, our data indicate that carbon source availability shapes T cell glucose metabolism and identifies lactate as a bioenergetic and biosynthetic fuel for CD8 + effector T cells., Competing Interests: Declaration of interests R.J.D. is a founder and consultant for Atavistik Biosciences and an advisor for Agios Pharmaceuticals, Nirogy Therapeutics, and Vida Ventures. R.G.J. is a scientific advisor for Agios Pharmaceuticals and Servier Pharmaceuticals and is a member of the Scientific Advisory Board of Immunomet Therapeutics., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Zhang et al. (2022) show that TCR signaling promotes the phosphorylation and activation of glycogen phosphorylase B (PYGB) in CD8 + memory T (Tmem) cells. PYGB-dependent glycogen mobilization provides a carbon source to support glycolysis and early Tmem cell recall responses., Competing Interests: Declaration of interests R.G.J. is a scientific advisor for Agios Pharmaceuticals and Servier Pharmaceuticals and is a member of the Scientific Advisory Board of Immunomet Therapeutics., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Growing evidence suggests that men prescribed a statin for cholesterol control have a lower risk of advanced prostate cancer (PCa) and improved treatment outcomes; however, the mechanism by which statins elicit their anti-neoplastic effects is not well understood and is likely multifaceted. Statins are potent and specific inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), the rate-limiting enzyme of the mevalonate (MVA) metabolic pathway. This two-part series is a review of the observational and experimental data on statins as anti-cancer agents in PCa. In this article, we describe the functional role that deregulated MVA metabolism plays in PCa progression and summarize the biological evidence and rationale for targeting the MVA pathway, with statins and other agents, for the treatment of PCa., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)